Although duodenal ulcer disease is a common problem, factors contributing to the pathogenesis of this disorder remain incompletely understood. Recent studies have shown that abnormally rapid emptying of gastric acid may be an important factor in the pathogenesis of this disease process. Under normal circumstances, duodenal acidification inhibits gastric motility. However, little is known about the mechanism responsible for this phenomenon. We hypothesize that secretin, a hormone released by duodenal acidification, inhibits gastric motility. This mechanism may be important to protect the duodenum from excessive amounts of acid. A failure of this normal feedback regulation of gastric motor activity occurs in patients with duodenal ulcer disease. To test this hypothesis parallel studies will be performed in healthy individuals and duodenal ulcer patients. We will first define the temporal relationship between gastric motor activities, duodenal pH, plasma motilin, and secretin during fasting. A low duodenal pH is expected to be accompanied by increase plasma secretin levels and inhibition of gastric motility, whereas in duodenal ulcer patients, persistently low duodenal pH may not be associated with disruption of gastric motility. This may result from impairment of secretin release or its action on gastric motility. The release of secretin by duodenal acidification in duodenal ulcer patients will be compared with healthy controls. The effect of exogenous secretin infusion on basal and motilin-stimulated gastroduodenal motility will be evaluated via dose response studies and the threshold of this response in ulcer patients will be compared to normal individuals. We will also investigate the effect of intraduodenal perfusion of bicarbonate and oral administration of cimetidine to suppress endogenous acid secretion on gastric motility. If our hypothesis is correct we would expect early occurrence of gastric phase III in the normal controls, whereas no effect is observed in duodenal ulcer patients. We will perform in vitro studies to examine the mechanism of action of secretin on gastric smooth muscle obtained from dogs and surgical specimens from patients with and without duodenal ulcer disease. Muscle tension-recording experiments will be performed to determine whether the inhibitory action of secretin represents a direct myogenic effect or a neurally mediated phenomenon. Secretin modulation of cholinergic transmission will be directly assessed by release of 3H-acetylcholine from the antral myenteric plexus. We will determine if the inhibitory action of secretin is impaired in gastric muscle obtained from duodenal ulcer patients and define the abnormalities. These studies will elucidate the basic mechanism responsible for rapid emptying of acid in duodenal ulcer patients and improve our understanding of the pathogenesis of duodenal ulcer disease.